Immune cell development, activation, and effector functions take place in primary, secondary, and tertiary lymphoid organs with different infrastructure, vasculature , and oxygen supply. We described the predominance of hypoxic conditions in lymphoid organs and demonstrated strong, differential and lineage-specific effects of physiologically relevant hypoxic conditions on regulation of T lymphocyte development and effector functions. Immune cells are exposed to low oxygen tensions as they develop and migrate between blood and different tissues, but the mechanisms by which lymphocytes adapt to hypoxia are poorly understood. Hypoxic conditions are known to lead to accumulation of extracellular adenosine and to stabilization of expression of Hypoxia Induced transcription Factors. Taken together with earlier observations of hypoxia in inflamed areas and of immunosuppressive effects of extracellular adenosine these data led us to suggest the key role of oxygen sensors, Hypoxia Induced Factors and adenosine (purinergic) receptors in physiological mechanisms of regulation of immune response in vivo. This hypothesis is supported by our recent studies of purinergic receptor gene deficient and HIF-1 deficient mice. Studies of adenosine receptor gene deficient mice demonstrated that the expression of A2a receptors is very tightly regulated. Properties of adenosine receptors are in agreement with the view that they play crucial role in regulation of inflammation and prevention of tissue damage and are consistent with the delayed negative feed-back mechanism of down regulation of pro-inflammatory cytokines secretion due to extracellular adenosine triggered purinergic receptor signaling in inflamed and hypoxic local tissue environment. These views formed the basis for the hypothesis that large solid tumors are surrounded by the shield of hypoxia-produced adenosine and the A2A receptor signaling through receptors on incoming anti-tumor T cells may inhibit them and thereby defend and protect tumors.